PROJECT SUMMARY This application is submitted in response to the RFA-DK-18-505 which is a limited competition opportunity to continue the support for the clinical centers of the NASH Clinical Research Network (NASH CRN). Although significant progress has been made in our understanding of this disease, numerous clinically important knowledge gaps remain which will be addressed by the NASH CRN during the next funding cycle. To meet the research objectives of the RFA-DK-18-505, we propose the following specific aims during the next funding period: Specific Aim 1: To successfully complete the following ongoing multicenter studies: (a) NAFLD Database 2, a longitudinal database of adults (n=2240) and children (n=949) with biopsy proven NAFLD, (b) STOP-NAFLD (n=110), a randomized, placebo-controlled, double-blind trial of losartan in children with biopsy proven NAFLD, and (c) VANISH (n=90), a randomized, placebo-controlled, double-blind trial of vatiquinone in adults with histologically characterized NAFLD; Specific Aim 2: To successfully complete ongoing ancillary and translational studies initiated during the current funding period by the IU Clinical Center; Specific Aim 3: Our central hypothesis is that FADS1 genetic variation is highly important for pediatric NAFLD. (A) To investigate the relationship between FADS1 genetic variation and liver histology in children with biopsy proven NAFLD. In more than 1,200 children with biopsy-proven NAFLD enrolled at multiple clinical centers in the United States, we will examine the genotype-phenotype correlation between FADS1 haplotype and liver histology in pediatric NAFLD. (B) To test the hypothesis that FADS1 genotype predicts the response to EPA/DHA treatment in children with NAFLD. We will test this hypothesis by conducting a clinical study in which 25 children with NAFLD who are homozygote for FADS1 low-activity haplotype (haplotype A/A18) and 25 children with NAFLD who are homozygote for normal-activity haplotype (haplotype D/D18) will receive fish oil (2-3 grams weight based) orally every day for 16 weeks. The EPA/DHA enrichment of erythrocytes following fish oil supplementation is the pharmacodynamic endpoint whereas changes in hepatic fat and serum aminotransferases are the efficacy endpoints. Specific Aim 4: To evaluate a novel PPAR ?/? agonist, saroglitazar, in adults with NASH. Saroglitazar is a highly attractive agent for further testing due to strong rationale for PPAR?/? agonism in improving NASH and robust preclinical and early clinical and safety data. In this randomized controlled trial, 160 adults with NASH meeting predefined eligibility will receive either saroglitazar (4 mg orally daily) or placebo for 72 weeks. The primary efficacy endpoint is improvement in centrally reviewed liver histology, defined as a decrease in NAFLD activity score (NAS) by at least 2 points without worsening of fibrosis.